A detailed investigation into the oxidation mechanism of Hantzsch 1,4-dihydropyridines by ethyl α-cyanocinnamates and benzylidenemalononitriles

Abstract

The mechanism for the oxidation of Hantzsch 1,4-dihydropyridine (HEH) by substituted ethyl α-cyanocinnamates (1) and benzylidenemalononitriles (2) has been critically investigated. Replacement of HEH by HEH-4,4-d₂ and HEH-N-d gave the observed kinetic isotope effects (KIE) of 5.3–6.0 and 1.2–1.3 for the reactions with 1 and 2, respectively, which suggests C₄–H bond dissociation is involved in the rate-limiting step and that the N–H bond dissociation is a non-rate-limiting step. The positive ρ values of 1.78 and 1.67 for the reactions of HEH with 1 and 2, respectively, clearly demonstrate the electrophilic nature of the substrates in the transition state (TS) and so indicate that the hydrogen lost from HEH must be a hydride-like species. Correlation analyses on the kinetics, KIE’s, and activation parameters showed excellent linear dependence on the electronic properties of remote substituents and added further credence to the proposed one-step hydride transfer mechanism. Detailed investigation of the activation parameters not only confirmed the direct H⁻_T mechanism, but also revealed experimentally, for the first time, an entropy-controlled compact TS for the HEH-modeled NAD(P)H oxidations.